This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. ABSTRACT Nonalcoholic fatty liver disease (NAFLD) is a common and increasingly recognized disorder characterized by macrovesicular accumulation of fat in hepatocytes, usually found in association with obesity, insulin resistance, and hyperlipidemia. This condition occurs in both adults and children, and arguably represents the most common cause of liver disease in pre-adolescence and adolescence. Insulin resistance and oxidative stress are considered to be the two most important mechanisms in the pathogenesis of NAFLD. We hypothesize that metformin and vitamin E will lead to sustained reduction in serum ALT with biopsy proven NASH through changes in insulin resistance or oxidative stress. The principal objective of this randomized, multicenter, double-masked, placebo-controlled trial is to evaluate whether 96 weeks of treatment with either metformin of vitamin E leads to sustained reduction in serum ALT in nondiabetic children with NAFLD compared to treatment with placebo. Other objectives include: To evaluate changes in serum AST and GGT To measure change in histologic feature scores of NAFLD To evaluate change in liver fibrosis, inflammation, or steatosis To evaluate change in insulin resistance indices To evaluate change in serum vitamin E levels To evaluate change in serum cytokine and fibrosis marker levels o To evaluate change in serum lipid profile To evaluate changes in anthropometric measurements (weight, BMI, waist to hip ratio, waist circumference, triceps skin fold thickness, total body fat, and distribution of fat) To measure change in quality of life scores To assess the role of diet and activity in the development and treatment of NAFLD To elucidate the natural history regarding clinical course and histology in untreated pediatric NAFLD (placebo plus diet and exercise advice) To obtain serum, liver, and DNA specimens from biopsy-confirmed pediatric patients with NAFLD for subsequent studies on etiopathogenesis. This NIH funded, multi center, Phase IV, drug trial has been recruiting patients since August of 2005 at eight institutions throughout the nation. While the goal is to recruit 180 patients (60 metformin, 60 vitamin E, and 60 placebo), recruitment has proven to be difficult. We aim to contribute 10 patients to this 96-week treatment trial.